Composition and Method for Improving Sleep Duration and Quality

ABSTRACT

An intervention for sleep disorders comprises collagen, a gelatin peptide, or the amino acid glycine; L-theanine; lactucopicrin, deoxylactucopicrin, or another lactucopicrin derivative; hyaluronic acid; epigallocatechin gallate; and quinic acid. The intervention helps regulate pro-inflammatory biomarkers that are often associated with insomnia development and progression. These biomarkers include cytokines and enzymes associated with tryptophan degradation. Inhibition of these enzymes and cytokines improves tryptophan availability and sleep quality, and allows individuals to sleep better with fewer side effects. The novel composition promotes high-quality, deep sleep.

This is a continuation of co-pending application Ser. No. 15/625,777,filed Jun. 16, 2017, now allowed with the issue fee paid; which claimsthe benefit under 35 U.S.C. § 119(e) of the Jul. 20, 2016 filing date ofprovisional patent application Ser. No. 62/364,474; the disclosures ofboth of which are hereby incorporated by reference in their entirety.

INTRODUCTION

Adequate sleep promotes health and the immune system. Sleep disordersand complaints can occur during childhood, adolescence or adult life [1,2]. Insufficient sleep affects children's physical health as well asemotional, cognitive and social development. In the youth and adolescentage group, commonly encountered sleep disorders include insomnia,sleep-disordered breathing, parasomnias, and sleep disturbancesassociated with medical and psychiatric disorders. Insufficient sleepaffects athletes' performance in many ways: it impairs reflexes,motivation, judgment, healing and even attention.

Sleep disturbances include insomnia, sleep apnea, sleep deprivation,restless legs syndrome, and sleep disorders resulting from chronicdiseases such as diabetes, cancer, Parkinson's disease, Alzheimer's andothers. Poor sleep disorders have negative influence on quality of lifeand are risk factors for the development of a myriad of chronicconditions including oxidative stress, pro-inflammation, fatigue,depression, obesity, metabolic syndrome, cardiovascular disease, andcancer. Sleep deprivation and disorders are common in Alzheimer'spatients [3-5]. Sleep deprivation exacerbates several chronic diseaseconditions including inflammatory bowel diseases. Sleep disorders areassociated with increased mortality [6]. Hypertension can predict theonset of sleep disorders, including insomnia and restless legs syndrome.

Chronic sleep shortage affects about 33% of the population inindustrialized nations [7, 8] and 50% of older adults [2].

Insomnia is defined as a subjective complaint of difficulty initiatingsleep, difficulty maintaining sleep, or early morning awakenings thatoccur at a minimum of 3 nights per week, for 3 months, and areassociated with significant daytime consequences [9]. Examples of thesedaytime consequences include difficulty concentrating, mooddisturbances, fatigue, and worry about sleep.

In older people, insomnia often is associated with other chronicconditions including physical and psychiatric ones. These conditions aremore common among older women than older men [10]. In older people, thenegative consequences of insufficient sleep include decreased quality oflife, risk for falls, psychological and physical difficulties, economicand social costs, risk for nursing home placement, and increasedmortality [2].

Many sleep disorders are inflammatory diseases. Cytokine levels play arole in normal sleep and sleep disturbances [11]. TNF-α and IL-1α areubiquitous and pleiotropic, they often co-exist, and both have thecapacity to induce each other and IL-6 [11]. TNF-α and IL-1β modulatenormal physiology including normal sleep, the innate arm of the immunesystem, and inflammatory disease processes and progression [12, 13].Both TNF-α and IL-1β are associated with sleep disorders such asnarcolepsy [14-16], inflammatory bowel disease [17-19], ulcerativecolitis [20], Crohn's disease [20-22], psoriasis [23, 24], Behçet'sdisease [25], arthritis [26, 27], amyotrophic lateral sclerosis [28],autoimmune diseases in general [29], fibromyalgia [30, 31],schizophrenia [32-34], illnesses that accompany malignancies [35], andcentral nervous system diseases such as multiple sclerosis [36, 37], andParkinson's disease and Alzheimer's disease [38-40].

Presently-Used Approaches to Managing Insomnia

Currently, insomnia is managed by over-the-counter, nonprescriptiondrugs such as melatonin or GABA; or by prescription drugs such aszolpidem (Ambien™) or Eszopiclone (Lunesta™). Melatonin is a naturallyoccurring hormone produced in the night to regulate circadian rhythms.Current reports suggest that melatonin is taken by adults and childrenabout equally. Recent studies suggest, however, that the long-termsafety of melatonin in children and adolescents is not known and thatmelatonin should not be used in this group [41]. Melatonin has beensuggested to help children with autism [42]. Studies that haveassociated melatonin found in foods with health benefits may be flawed[43]. Drugs for insomnia have both beneficial effects [44] and sideeffects, sometimes serious side effects [45-48]. Insomnia can also bemanaged by tart cherry juice, which can be consumed at the level of 2cups a day [49]. The high sugar content and cost of cherry juice limitsits use by individuals with diabetes and consumers concerned with highsugar levels in foods.

A recent review of the efficacy of Zolpidem, L-theanine, and othercompounds on insomnia in children with attention-deficit/hyperactivitydisorder (ADHD) reported that both compounds “displayed a poor responsein reducing sleep latency and increasing total sleep time, howeverL-theanine did produce an increase in sleep efficiency. Zolpidemproduced high levels of side effects, leading to the largest dropoutrate of all five studies. Clonidine reduced insomnia; and melatonin alsoexhibited a positive response, with reduced sleep latency, higher totalsleep time, and higher sleep efficiency” [48]. The side effects ofmelatonin include headache, and theanine is a tranquilizer [50, 51].

R. Street et al., “Cichorium intybus: Traditional uses, phytochemistry,pharmacology, and toxicology,” Evidence-Based Complementary andAlternative Medicine, vol. 2013, article ID 579319, 13 pages gives areview of traditional uses of chicory, its pharmacology, and relatedtopics [52]. Chicory is used in traditional medicine, and is said to beuseful for conditions ranging from uterine cancer, digestive disorders,high blood pressure, gout, malaria, stimulating appetite, gallstones,jaundice, liver diseases, and many others. Scientific studies have beenconducted to investigate chicory's or its components' antibacterialactivity, antihelmintic activity, antimalarial activity,hepatoprotective activity, antidiabetic activity, gastroprotectiveactivity, anti-inflammatory activity, analgesic activity, antioxidantactivity, tumor-inhibitory activity, antiallergic activity, and otheractivities.

J. Barrett et al., “To sleep or not to sleep: A systematic review of theliterature of pharmacological treatments of insomnia in children andadolescents with attention-deficit/hyperactivity disorder,” J. Child andAdolescent Psychopharmacology, vol. 23, pp. 640-647 (2013) reviewstreatments that have been used in ADHD children and adolescents to treatinsomnia, including Zolpidem, theanine, clonidine, and melatonin [48].Theanine was reported to yield a poor response both in reducing sleeplatency and in increasing total sleep time, although it did increasesleep efficiency and reduce nocturnal activity.

M. Lyon et al., “The effects of L-theanine (Suntheanine® on objectivesleep quality in boys with attention deficit hyperactivity disorder(ADHD): a randomized, double-blind, placebo-controlled clinical trial,”Alt. Med. Rev., vol. 16, pp. 348-354 (2011) reported that theanineimproved sleep percentage and sleep efficiency in boys with ADHD [53]. Anon-significant trend for less activity during sleep was observed. Sleeplatency and other sleep parameters were unchanged.

T. Rao, “In search of a safe natural sleep aid,” J. Am. Coll. Nutr.,vol. 34, pp. 436-447 (2015) reports that L-theanine has anxiolyticeffects that promote quality of sleep [54].

M. Bannai et al., “New therapeutic strategy for amino acid medicine:Glycine improves the quality of sleep,” J. Pharmacol. Sci., vol. 118,pp. 145-148 (2012) reported that glycine induces a decrease in core bodytemperature, and that it improves subjective sleep quality [55]. Seealso M. Bannai et al., “The effects of glycine on subjective daytimeperformance in partially sleep-restricted healthy volunteers,” Frontiersin Neurology, vol. 3, article 61, 8 pages (2012) [8].

Sleep disorders are becoming more common. The economic and social burdenof sleep disorders is enormous. There is an unfilled need for improvedmethods for treating sleep disorders, with minimal side effects.

We have discovered an intervention for sleep disorders based on novelcombinations of dietary bioactive compounds. The new intervention helpsregulate pro-inflammatory biomarkers that are often associated withinsomnia development and progression. These biomarkers include cytokinesand enzymes associated with tryptophan degradation. Inhibition of theseenzymes and cytokines improves tryptophan availability and sleepquality, and allows individuals to sleep better with fewer side effects.The novel composition promotes high-quality, deep sleep.

BIOACTIVES USED IN THE FORMULATION

The combination of the present invention employs two or more; preferablythree or more; more preferably four or more; and most preferably all ofthe following components: (1) Collagen peptides, i.e., peptidesresulting from the partial hydrolysis of collagen, generally having amolecular weight less than 3,500 Dalton, preferably less than 2,000Dalton and having a high level of glycine (see FIG. 1). The collagen maybe derived from any convenient, economical source, for example beefcollagen, porcine collagen, poultry collagen, or marine-source collagen.On an industrial scale, once a collagen source has been selected,enzymatic hydrolysis can be performed using single or multiple, specificor non-specific proteases. A heat pre-treatment may be applied todenature collagen into gelatin, which can likely be used as a source of“collagen peptides.” Enzymes that may be used in the hydrolysis include,for example trypsin, alcalase, flavorzyme, pronase, pepsin, properase E,pronase, collagenase, bromelain Amano protease, and papain or acombination of these enzymes. Optional post-hydrolysis processing stepsto obtain or concentrate bioactive peptides may include one or more ofthe following: ultrafiltration, dialysis, size-exclusion chromatography,and ion-exchange chromatography [56]. The resulting small, bioactivepeptides (preferably of less than 2,000 Daltons) are rich in glycine,and some of the peptides may have antioxidative or anti-hypertensiveactivities [57-59]. To the inventors' knowledge, neither collagen norcollagen peptides nor glycine has previously been reported to reduceinsomnia.

Collagen is high in glycine. Collagen peptides, rich in glycine, mayhelp inhibit the angiotensin-converting enzyme, which can increase bloodpressure [56]. Other sources rich in glycine may be used instead of, orin addition to the collagen peptides. Collagen is also low inphenylalanine, which is advantageous for phenylketonurics. The manner ofmaking the peptides from collagen, such that they generally have amolecular weight less than 3,500 Dalton, preferably less than 2,000Dalton is a matter of convenience, and may be carried out through anymeans known in the art. The peptides may optionally be denatured, e.g.,peptides derived from gelatin. (2) High- or medium-weight hyaluronicacid (or hyaluronan), an optional ingredient, may play a role inpromoting sleep due to its anti-inflammatory properties [60]. It ispreferred to use the native hyaluronan, rather than its fragments. Tothe inventors' knowledge, hyaluronic acid has not previously beenreported to have an effect on sleep. Preferably, the hyaluronic acid andthe collagen peptides are both supplied in the same collagen peptidecomposition; hyaluronic acid is a naturally-occurring component ofcollagen. (3) Epigallocatechin gallate (EGCG), which inhibits enzymesassociated with tryptophan degradation, and is preferably supplied as atea extract, preferably a green tea extract, depleted in caffeine. EGCGcan also be obtained separately from commercial sources. To theinventors' knowledge, EGCG has not previously been reported to have aneffect on sleep. Green tea extracts high in EGCG and theanine arecommercially available. (4) Theanine, which calms, is preferablysupplied as a tea extract, preferably a green tea extract, depleted incaffeine. Preferably, the EGCG and theanine are both supplied in thesame tea extract, preferably a green tea extract, depleted in caffeine.EGCG can also be obtained separately from commercial sources. (5)Lactucin and its derivative lactucopicrin have demonstrated excellentanalgesic and sedative properties in an in vivo animal model [61].Lactucin, its derivative deoxylactucin, lactucopicrin, or lactucopicrinderivatives (such as deoxylactucopicrin), or both, preferably suppliedas a chicory extract (CE), most preferably a lightly-roasted chicoryextract, or even raw chicory rich in inulin. We have found that longerroasting times deplete the desired components of CE, and that it ispreferable to use a lighter, shorter roasting time than has typicallybeen used for chicory employed as a coffee substitute or coffeeflavoring agent. Longer roasting times are preferred when chicory isused as a coffee substitute or additive, because the product tastesunpleasantly bitter with shorter roasting times. The extract derivedfrom light-roasted chicory is bitter and contains sesquiterpenes such aswater-soluble lactucin and deoxylactucin, and very small amounts ofrelatively water-insoluble lactucopicrin and deoxylactucopicrin. Eventhough lactucopicrin has low solubility in water, it is very bitter evenat low concentrations.) The preferred roasting temperature is 150-170°C., for 30 minutes or less. It is also possible to reduce or even omitthe roasting step, to enhance the levels of lactucin, lactucopicrin andassociated compounds, although the taste might then be objectionable tosome consumers. To the inventors' knowledge, lactucin, lactucopicrin,and their derivatives have not previously been reported to have aneffect on sleep. (6) Quinic acid. Quinic acid is preferably supplied asa chicory extract. Quinic acid can also be obtained separately fromcommercial sources. To the inventors' knowledge, quinic acid has notpreviously been reported to have an effect on sleep.

The combination is optionally flavored to enhance its palatability,preferably with natural flavoring agents.

Most of the components of the novel combination have not previously beenreported to have an effect on sleep. In fact, to the inventors'knowledge, of all the components, only theanine has previously beenassociated with any effect on sleep. Further, there is a synergy, inthat the effect of the combination is much greater than would beexpected from the properties of the individual components.

The novel formulation enhances an early onset of sleep, and improvessleep depth, quality, and duration and reduces fatigue the next day. Theformulation is also useful in reducing symptoms of sleep apnea. Thecombination possesses a synergy in these effects that is unmatched byany of the individual compounds, and that would not be expected fromtheir individual properties. Indeed, none of the individual componentsalone has a strong effect on sleep onset, duration, or quality at all,although the novel combination does: (1) Collagen or gelatin peptidesalone do not enhance sleep onset, depth, efficiency, or duration. Thepeptides alone do not improve sleep after awakening in the middle of thenight. (2) EGCG alone does not enhance sleep onset, depth, efficiency,or duration. EGCG alone does not improve sleep after awakening in themiddle of the night. (3) Theanine alone does not enhance sleep onset,depth, efficiency, or duration. Theanine alone does not improve sleepafter awakening in the middle of the night. (4) CE alone does notenhance sleep onset, depth, efficiency, or duration. CE alone does notimprove sleep after awakening in the middle of the night.

However, the novel combination of these components substantiallyenhances sleep onset, depth, efficiency, and duration; and improvessleep after awakening in the middle of the night. The novel combinationalso reduces sleepiness and fatigue the following day.

Based on preliminary reports from individuals who have tried variouscombinations (n=12, not statistically validated at this point), the mosteffective combination for providing deep and restful sleep was collagenpeptide+hyaluronic acid+theanine+EGCG+Chicory extract; followed bycollagen peptide+hyaluronic acid+theanine+Chicory extract; followed byTheanine+Glycine (free amino acid)+Chicory Extract.

EGCG inhibits Janus kinase 3, indoleamine dioxygenase, TNF-α, IL-6,IL-1α, and histamine, which may have an effect on improving sleep depthand quality. See the data reported below. To the inventors' knowledge,EGCG has not previously been reported to have an effect on sleep onset,efficiency, depth or duration.

Collagen peptides, rich in glycine, lower blood pressure and may lowerbody temperature. It is known that the free amino acid glycine can lowerbody temperature, and that body temperature is reduced during sleep. SeeBannai and Kawai (2012) [55]. To the inventors' knowledge, similareffects with glycine-rich peptides have not been reported. Glycine doesnot, however, reduce awakening during the night.

CE is anti-oxidative, and is known to inhibit TNF-α [52]. Chicory isprotective against oxidative stress by scavenging reactive oxygenspecies, boosting the endogenous antioxidant defense system, and byupregulating genes that encode antioxidant enzymes. See El-Sayed et al.(2015) [62]; Aquil et al. (2006) [63].

A series of in vitro tests were conducted, using levels of componentsthat would be expected to approximate the concentrations that would beseen in vivo following oral consumption of 2 fluid ounces of the novelcomposition by a 70 kilogram individual.

Lab Results

-   -   a. Inhibition of Janus kinase 3 (Jak3) by EGCG, CE, or a mixture        of EGCG and CE. Jak3 is expressed solely in immune cells. Jak3        expression is an upstream event for the activation of TNF-α and        subsequent cytokines such as IL-6. HT-29 colon cancer cells in        T-75 flasks were stimulated by LPS (control). HT-29 cells in        T-75 flasks were also stimulated by LPS and treated with EGCG        (Treatment 1=20 μM (E1), Treatment 2=35 μM (E2), or Treatment        3=50 μM (E3)), CE (extract from 3 g (C1), 6 g (C2), or 10 g (C3)        of light roasted chicory), or combinations of the respective        low, medium, and high concentrations of EGCG and CE (E1C1, E2C2,        or E3C3). C1, C2, or C3 concentrations approximated the levels        that would be expected following consumption of 2 fluid ounces        of the novel composition by a 70 kilogram individual. C1, C2,        and C3 were lyophilized and dissolved in the DMEM+10% FBS        medium, filtered and added to the HT-29 cells and LPS in the        medium. All treatments were in triplicates. Results are        presented in FIG. 2. EGCG and CE both inhibited Jak3 expression        in a dose-dependent manner, and the effect of the combination        was synergistic.    -   b. Anti-histamine activity of EGCG, CE, or a mixture of EGCG and        CE.        -   HeLa cells were used as a model for determining the            anti-histamine activity of EGCG, CE or the combination            EGCG-CE. HeLa cells were treated with 1 μmol/L of histamine            in absence (negative control) or presence of the EGCG at            (Treatment 1=20 μM (E1), Treatment 2=35 μM (E2), or            Treatment 3=50 μM (E3)) for 18 h. Histamine H1 receptor            antagonist mepyramine maleate and histamine 4 receptor            antagonist JNJ-7777120 were also used in separate treatments            as positive controls. The effects of the treatments on            histamine activity were determined by the inhibition of            COX-2 expression. Results are presented in FIG. 3. EGCG            inhibited COX-2 expression in a dose-dependent manner,            although not as strongly as did the positive controls. CE            also inhibited COX-2 levels although not as strongly as did            mepyramine maleate or JNJ-7777120. The combination EGCG-CE            synergistically inhibited COX-2.    -   c. Inhibition of TNF-α, IL-la, and IL-6 by EGCG, CE, or a        mixture of EGCG and CE.        -   Supernatants from HT-29 cell cultures control or cell            cultures treated with LPS were used to determine levels of            TNF-α, IL-1β or IL-6 by ELISA. Supernatant was mixed with            EGCG at (Treatment 1=20 μM (E1), Treatment 2=35 μM (E2), or            Treatment 3=50 μM (E3)). The effective concentrations of            TNF-α, IL-1β or IL-6 in supernatants were calculated using a            standard curve developed using known standards of TNF-α,            IL-1β or IL-6. Results are presented in FIGS. 4, 5, and 6,            respectively. EGCG and CE each inhibited the activity of            each of TNF-α, IL-1β and IL-6 in a dose-dependent manner;            and the effect of the combination of EGCG and CE was            synergistic and dose-dependent.

Without wishing to be bound by this hypothesis, we propose the followingmechanism of action: Janus kinase enzyme occurs in a cascade upstream ofthe enzyme indoleamine dioxygenase; the latter degrades tryptophan, anamino acid associated with sleep. Inhibiting Janus 3 kinasedown-regulates expression of indoleamine dioxygenase, which in turnsdecreases tryptophan degradation, and higher circulating levels oftryptophan enhance sleep. Further, there is an association betweenhistamine levels and lack of sleep. Anti-histaminic compounds can alsohelp individuals to fall asleep.

Formulations

Exemplary Formulations

Bacteria-free water is obtained by filtration or boiling. Thebacteria-free water is mixed with the other ingredients in the preferredranges: 0.5 to 12 g collagen peptide (or 0.5 to 5 g glycine as aminoacid); 100 to 500 mg theanine (preferably as tea extract); 50 to 300 mgEGCG (preferably as tea extract); 1-10 g chicory extract. The mixture isoptionally sweetened and flavored before serving. Nutritive ornon-nutritive sweeteners known in the art may be added, such as sucrose,erythritol, or stevia. Flavorings known in the art may be added such asmocha, vanilla, caramel, hazelnut, peach, orange, pina colada, berries,and others. The final volume is brought to 60 ml and is then ready toserve. The nightly dose is about 60 mL. The solution has a shelf life ofat least one year at room temperature, and longer if refrigerated.Nevertheless, for enhanced stability it is preferred to maintain theformulation as a powder until shortly before use. If the container inwhich the powder is stored is not well-sealed (or supplied with aseparate desiccant), the powder can absorb moisture in a humidenvironment. The liquid can be susceptible to mold or yeast growth,unless pasteurized and stored in a sealed container. The formulation maybe presented as a 30-60 mL (1-2 fluid ounce) beverage, or as a driedpowder or tablet.

A preferred method for preparing the formulation is to percolate hotwater through the source materials. We found that percolation worksbetter than brewing, presumably because the effective contact timebetween the water and the components is greater. Surprisingly, we foundthat using filter paper (as might be used in brewing) is undesirable;the filter paper evidently absorbs at least some of the activeingredients. Perhaps small suspended particles are important; or perhapsthe fibers of the paper adsorb active compounds. In a future experiment(not yet carried out) we will test an inert filter, such as acommercially-available gold-plated coffee filter.

The liquid or dry formulation is shelf-stable for at least one year atroom temperature, if properly sealed. Optionally, stability may beenhanced by adding stabilizers known in the art, for example cultureddextrose or potassium sorbate.

Preparation of Chicory Extract (CE) Powder

Raw or lightly roasted chicory roots (3 to 10 g) are ground, and thenpercolated for 15-50 min in five to ten times their volume in water,filtered, cooled, and spray-dried with 15-35% low dextrose equivalent(DE) maltodextrin or tricalcium phosphate. Other methods of drying canbe used, for example lyophilization, but spray-drying is preferred.Percolation is a preferred method to extract the chicory roots. Brewingcan also be used. The dried powder is rich in bitter sesquiterpenes suchas lactucin, lactucopicrin, and their derivatives; inulin; pectin;quinic acid; chicoric acid; and chlorogenic acid. Cf. U.S. patentapplication publication no. US20160095337A1, for the preparation oflow-bitter chicory products.

The spray dried powder can be used in formulations including not onlyformulations for managing insomnia, but also for managing orameliorating other conditions such as Parkinson's disease, inflammatorybowel disease, multiple sclerosis, arthritis, diabetes, atherosclerosis,cancer, obesity, autism, ADHD, Alzheimer's, fibromyalgia, sleep apnea,and insulin resistance.

Anecdotal Sleep Reports

A 7-day anecdotal sleep study was performed with 14 patients.

Other anecdotal sleep studies have been carried on for less than 7 daysby over 40 additional individuals, and they have reported generallysimilar results.

Fourteen patients were provided a 7-day dose of the sleep formulation;they logged their observations and reported them. Following are selectedextracts from their self-reported observations:

Participant #1

Slept well through the night, no stress. A little bit of migraine but Itook care of it.

Participant #2

I have slept better than usual this week. Even when I woke up after 1:00a.m. was able to go back to sleep until the morning and go to workwithout feeling tired and sleepy.

Participant #3

For the entire week I took the beverage 1-2 hours before bedtime, Islept better than before. I woke up but was able to get back to sleepfaster.

Participant #4

I wake a little less. Seemed to fall back asleep quicker and sleeplonger. Seem to remember dreams much better.

Participant #5

I am less sleepy in the mornings than I was before (even when going tobed at the same time). My sleep quality was better than before.

Participant #6

I feel like I am sleeping better with this product.

Participant #7

I go to bed at 9:00 p.m., and typically wake up at 1:00 a.m. and nevergo back to sleep until I drive to work in the morning. This beveragehelped me a bit. I was still waking up at 1:00 a.m. or 2:00 a.m. but wasable to sleep again, wake up in the morning and have a better day thanbefore taking this beverage.

Participant #9

Slept better than usual, woke up sometimes at night, but did go back tosleep. It was not perfect but better than before when I could just notfall asleep at all.

Participant #10

Worked better than chamomile. I could sleep better and not feel sleepyduring the day.

Participant #11

Sleep is a problem for me. I tried this formulation and on night one Iwas sleeping better than ever before. Can you make 10 gallons? How muchwill you charge?

Participant #12

This male has a hard time sleeping. He tried it, slept very well, wokeup around 1 a.m. but was able to go back to sleep again.

Participant #13

I like the stuff. I slept very well and will use it again.

Participant #14

Please send me a 2-week serving because I am sleeping better.Results from another preliminary study are summarized in Table 1:

TABLE 1 Effect of sleep-aid formulation with E3 and C3 on SubjectiveSleep Quality in 56 volunteer participants with sleep problems QuestionNumber Question Response 1 How difficult was it to fall asleep Notdifficult (96%) after taking the sleep formulation? 2 How long did ittake you to fall Within 30 min (96%) asleep? 3 How deep was your sleep?Very deep (96%) 4 How often did you wake up at night? As usual (100%) 5Did you return to sleep after Yes (100%) awakening in the middle of thenight? 6 Was it easy to wake up in the Yes (100%) morning after takingthe sleep formulation? 7 How was your day compared to days Better (96%)after taking other sleep aids? 8 Did you feel daytime sleepiness Not atall (100%) after a night with the sleep formulation? 9 Did you feel anyheadache or side No (100%) effect after taking the sleep formulation? 10Overall, how satisfied were you with Very (96%) the sleep formulation?

As used herein, an “effective amount” of a composition refers to aquantity of the composition sufficient to be effective to enhance theduration, quality, or onset of sleep to a clinically significant degree;or alternatively, to a statistically significant degree as compared tocontrol. “Statistical significance” means significance at the P<0.05level, or such other measure of statistical significance as would beused by those of skill in the art of biomedical statistics in thecontext of the treatment. An “effective amount” can vary with the age,general condition of the subject, the severity of the condition beingtreated, the duration of the treatment, the nature of any concurrenttreatment, the pharmaceutically acceptable carrier used, and likefactors within the knowledge and expertise of those skilled in the art.As appropriate, an “effective amount” in any individual case can bedetermined by routine experimentation.

The complete disclosures of all references cited in this application arehereby incorporated by reference. In the event of an otherwiseirreconcilable conflict, however, the present specification shallcontrol.

EMBODIMENTS (SET A)

1. A composition comprising at least two of three Components selectedfrom the group consisting of: (Component 1) Collagen or gelatin peptidesor glycine amino acid having a molecular weight less than 3500 Dalton,preferably less than 2000 Dalton; (Component 2) L-Theanine; and(Component 3) Lactucopicrin or lactucopicrin derivatives, such aslactucopicrin or deoxylactucopicrin.2. The composition of Embodiment 1, additionally comprising at least oneadditional Component selected from the group consisting of: (Component4) hyaluronic acid, (Component 5) epigallocatechin gallate, and(Component 6) quinic acid.3. The composition of Embodiment 1, wherein said composition compriseseach of Component 1, Component 2, and Component 3.4. The composition of Embodiment 3, additionally comprising at least oneComponent selected from the group consisting of: (Component 4)hyaluronic acid, (Component 5) epigallocatechin gallate, and (Component6) quinic acid.5. The composition of Embodiment 4, wherein said composition compriseseach of Component 4, Component 5, and Component 6.6. The composition of Embodiment 5, wherein said composition comprisesextract of tea (Camellia sinensis) and extract of chicory (Cichoriumintybus).7. The composition of Embodiment 1, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.8. The composition of Embodiment 2, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.9. The composition of Embodiment 3, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.10. The composition of Embodiment 4, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.11. The composition of Embodiment 5, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.12. The composition of Embodiment 6, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.13. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 1.14. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 2.15. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 3.16. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 4.17. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 5.18. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 6.19. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 7.20. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 8.21. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 9.22. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 10.23. A method for treating the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 11.24. A method for treating the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 12.

EMBODIMENTS (SET B)

1. A composition comprising at least two Components selected from thegroup consisting of: (Component 1) Collagen or gelatin peptides having amolecular weight less than 3500 Dalton, preferably less than 2000Daltons, or glycine amino acid (0.5-12 g); (Component 2) L-Theanine(100-500 mg); and (Component 3) lactucin (0.2 mg-2.0 mg), Lactucopicrin(0.05 mg-0.2 mg) or their derivatives including 8-deoxylactucin (0.05mg-0.2 mg), 11, 13-dihydrolactucin (0.1-0.5 mg), and 11,13-dihydrolactucopicrin (0.05 mg-0.1 mg). Higher levels of these bittercompounds can be obtained by extended brewing/percolation times, e.g.,more than 50 min.2. The composition of Embodiment 1, additionally comprising at least oneComponent selected from the group consisting of: (Component 4)hyaluronic acid (4-150 mg), (Component 5) epigallocatechin gallate(100-300 mg), and (Component 6) quinic acid (5-15 mg).3. The composition of Embodiment 1, wherein said composition comprisesComponent 1, Component 2, and Component 3.4. The composition of Embodiment 3, additionally comprising at least oneComponent selected from the group consisting of: (Component 4)hyaluronic acid, (Component 5) epigallocatechin gallate, and (Component6) quinic acid.5. The composition of Embodiment 4, wherein said composition comprisesComponent 4, Component 5, and Component 6.6. The composition of Embodiment 5, wherein said composition comprisesextract of tea (Camellia sinensis) and extract of chicory (Cichoriumintybus).7. The composition of Embodiment 1, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.8. The composition of Embodiment 2, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.9. The composition of Embodiment 3, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.10. The composition of Embodiment 4, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.11. The composition of Embodiment 5, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.12. The composition of Embodiment 6, additionally comprising water, anutritive or non-nutritive sweetener, and a flavoring agent; whereinsaid flavoring agent is not one of said Components.13. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 1; preferably 1 to 2 fluid ounces,preferably 2 fluid ounces.14. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 2.15. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 3.16. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 4.17. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 5.18. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 6.19. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 7.20. A method for improving the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 8.21. A method for managing the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 9.22. A method for managing the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 10.23. A method for managing the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 11.24. A method for managing the symptoms of a sleep disorder in a human,said method comprising administering to the human an effective amount ofthe composition of Embodiment 12.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Gel electrophoresis of collagen and collagen peptides todetermine the approximate size of the collagen peptides. Lane 1 had amixture molecular weight markers/standards (STND) to determine theapproximate sizes of other protein or peptide molecule(s) on the gel. Inlane 2, 20 mg of collagen peptides were loaded and separated byelectrophoresis. No peptides were seen larger than 3.5 kDa. Lane 3contained collagen at 1 mg/ml. The band above 160 kDa showed thepresence of collagen before hydrolysis. Lane 4 contained collagenpeptides at 10 mg/ml. Similar to lane 2, there were no peptides largerthan 3.5 kDa. Lane 2 contained twice the amount of collagen that wasloaded in Lane 4. The results showed that the mixture contained nopeptides higher than 3.5 kDa.

FIG. 2: Inhibition of JAK3 kinase by green tea EGCG. Effect of EGCG atdifferent concentrations, chicory extract (C) at differentconcentrations, or the combination of EGCG and chicory extract (E-C) atdifferent concentrations on JAK3 kinase levels in HT-29 cell culturetreated with LPS.

FIG. 3: Effect of EGCG at different concentrations, chicory extract (C)at different concentrations, or the combination of EGCG and chicoryextract (E-C) at different concentrations on COX-2 levels in HeLa cellculture treated with LPS. Comparison was made with mepyramine maleate ashistamine H1 receptor antagonist as positive control. Comparison wasalso made with histamine 4 receptor antagonist JNJ-7777120 as positivecontrol.

FIG. 4. Effect of EGCG at different concentrations, chicory extract (C)at different concentrations, or the combination of EGCG and chicoryextract (E-C) at different concentrations on TNF-alpha levels in HT-29cell culture treated with LPS.

FIG. 5: Effect of EGCG at different concentrations, chicory extract (C)at different concentrations, or the combination of EGCG and chicoryextract (E-C) at different concentrations on IL-113 levels in HT-29 cellculture treated with LPS.

FIG. 6: Effect of EGCG at different concentrations, chicory extract (C)at different concentrations, or the combination of EGCG and chicoryextract (E-C) at different concentrations on IL-6 levels in HT-29 cellculture treated with LPS.

LITERATURE CITED

-   [1] Baweja R, Calhoun S, Singareddy R. Sleep problems in children.    Minerva pediatrica 2013; 65:457-472.-   [2] Rodriguez J C, Dzierzewski J M, Alessi C A. Sleep problems in    the elderly. The Medical clinics of North America 2015; 99:431-439.-   [3] Beaulieu-Bonneau S, Hudon C. Sleep disturbances in older adults    with mild cognitive impairment. International psychogeriatrics/IPA    2009; 21:654-666.-   [4] Cochen V, Arbus C, Soto M E et al. Sleep disorders and their    impacts on healthy, dependent, and frail older adults. The journal    of nutrition, health & aging 2009; 13:322-329.-   [5] Vecchierini M F. [Sleep disturbances in Alzheimer's disease and    other dementias]. Psychologie & neuropsychiatrie du vieillissement    2010; 8:15-23.-   [6] Grandner M A. Addressing sleep disturbances: an opportunity to    prevent cardiometabolic disease? Int Rev Psychiatry 2014;    26:155-176.-   [7] Terzano M G, Rossi M, Palomba V et al. New drugs for insomnia:    comparative tolerability of zopiclone, zolpidem and zaleplon. Drug    safety 2003; 26:261-282.-   [8] Bannai M, Kawai N, Ono K et al. The effects of glycine on    subjective daytime performance in partially sleep-restricted healthy    volunteers. Frontiers in neurology 2012; 3:61.-   [9] Rodriguez J C, Dzierzewski J M, Alessi C A. Sleep Problems in    the Elderly. Medical Clinics of North America 2014.-   [10] Krishnan V, Collop N A. Gender differences in sleep disorders.    Current opinion in pulmonary medicine 2006; 12:383-389.-   [11] Clark I A, Vissel B. Inflammation-sleep interface in brain    disease: TNF, insulin, orexin. Journal of neuroinflammation 2014;    11:51.-   [12] Krueger J M, Clinton J M, Winters B D et al. Involvement of    cytokines in slow wave sleep. Progress in brain research 2011;    193:39-47.-   [13] Mullington J M, Simpson N S, Meier-Ewert H K, Haack M. Sleep    loss and inflammation. Best practice & research. Clinical    endocrinology & metabolism 2010; 24:775-784.-   [14] Himmerich H, Beitinger P A, Fulda S et al. Plasma levels of    tumor necrosis factor alpha and soluble tumor necrosis factor    receptors in patients with narcolepsy. Archives of internal medicine    2006; 166:1739-1743.-   [15] Chrousos G, Vgontzas A N, Kritikou I. HPA Axis and Sleep. In:    Endotext. Edited by: De Groot U, Beck-Peccoz P, Chrousos G et al.    South Dartmouth (MA): 2000.-   [16] Tanaka S, Honda M, Toyoda H, Kodama T. Increased plasma IL-6,    IL-8, TNF-alpha, and G-CSF in Japanese narcolepsy. Human immunology    2014; 75:940-944.-   [17] Koutroubakis I E, Ramos-Rivers C, Regueiro M et al. The    Influence of Anti-tumor Necrosis Factor Agents on Hemoglobin Levels    of Patients with Inflammatory Bowel disease. Inflammatory bowel    diseases 2015.-   [18] Jiang W, Li X. Molecular Analysis of Inflammatory Bowel    Disease: Clinically Useful Tools for Diagnosis, Response Prediction,    and Monitoring of Targeted Therapy. Molecular diagnosis & therapy    2015.-   [19] Ali T, Orr W C. Sleep disturbances and inflammatory bowel    disease. Inflammatory bowel diseases 2014; 20:1986-1995.-   [20] Lahad A, Weiss B. Current therapy of pediatric Crohn's disease.    World journal of gastrointestinal pathophysiology 2015; 6:33-42.-   [21] van Dullemen H M, van Deventer S J, Hommes D W et al. Treatment    of Crohn's disease with anti-tumor necrosis factor chimeric    monoclonal antibody (cA2). Gastroenterology 1995; 109:129-135.-   [22] Randall C W, Vizuete J A, Martinez N et al. From historical    perspectives to modern therapy: a review of current and future    biological treatments for Crohn's disease. Therapeutic advances in    gastroenterology 2015; 8:143-159.-   [23] Chaudhari U, Romano P, Mulcahy L D et al. Efficacy and safety    of infliximab monotherapy for plaque-type psoriasis: a randomised    trial. Lancet 2001; 357:1842-1847.-   [24] Mitsui A, Tada Y, Takahashi T et al. Serum IL-33 levels are    increased in patients with psoriasis. Clinical and experimental    dermatology 2015.-   [25] Caso F, Costa L, Rigante D et al. Biological treatments in    Behçet's disease: beyond anti-TNF therapy. Mediators of inflammation    2014; 2014:107421.-   [26] Paramarta J E, Baeten D, De Rycke L. Synovial Tissue Response    to Treatment with TNF Blockers in Peripheral Spondyloarthritis. The    open rheumatology journal 2011; 5:127-132.-   [27] Elliott M J, Maini R N, Feldmann M et al. Randomised    double-blind comparison of chimeric monoclonal antibody to tumour    necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.    Lancet 1994; 344:1105-1110.-   [28] Kiaei M, Petri S, Kipiani K et al. Thalidomide and lenalidomide    extend survival in a transgenic mouse model of amyotrophic lateral    sclerosis. The Journal of neuroscience: the official journal of the    Society for Neuroscience 2006; 26:2467-2473.-   [29] Wang D, Li Y, Liu Y, Shi G. The Use of Biologic Therapies in    the Treatment of Rheumatoid Arthritis. Current pharmaceutical    biotechnology 2014; 15:542-548.-   [30] Togo F, Natelson B H, Adler G K et al. Plasma cytokine    fluctuations over time in healthy controls and patients with    fibromyalgia. Exp Biol Med (Maywood) 2009; 234:232-240.-   [31] Bazzichi L, Rossi A, Massimetti G et al. Cytokine patterns in    fibromyalgia and their correlation with clinical manifestations.    Clinical and experimental rheumatology 2007; 25:225-230.-   [32] Suvisaari J, Loo B M, Saarni S E et al. Inflammation in    psychotic disorders: a population-based study. Psychiatry Res 2011;    189:305-311.-   [33] Dean B, Gibbons A S, Tawadros N et al. Different changes in    cortical tumor necrosis factor-alpha-related pathways in    schizophrenia and mood disorders. Molecular psychiatry 2013;    18:767-773.-   [34] Song X Q, Chen X M, Zhang W et al. [Study of adiponectin,    IL-1beta, IL-6 and TNF-alpha in first episode drug nasmall yi,    Ukrainianve schizophrenia]. Zhonghua yi xue za zhi 2013;    93:3256-3260.-   [35] Oliff A, Defeo-Jones D, Boyer M et al. Tumors secreting human    TNF/cachectin induce cachexia in mice. Cell 1987; 50:555-563.-   [36] Ramirez-Ramirez V, Macias-Islas M A, Ortiz G G et al. Efficacy    of fish oil on serum of TNF alpha, IL-1 beta, and IL-6 oxidative    stress markers in multiple sclerosis treated with interferon    beta-1b. Oxidative medicine and cellular longevity 2013;    2013:709493.-   [37] Wen S R, Liu G J, Feng R N et al. Increased levels of IL-23 and    osteopontin in serum and cerebrospinal fluid of multiple sclerosis    patients. Journal of neuroimmunology 2012; 244:94-96.-   [38] Adibhatla R M, Hatcher J F. Altered lipid metabolism in brain    injury and disorders. Sub-cellular biochemistry 2008; 49:241-268.-   [39] Singhal G, Jaehne E J, Corrigan F et al. Inflammasomes in    neuroinflammation and changes in brain function: a focused review.    Frontiers in neuroscience 2014; 8:315.-   [40] Rubio-Perez J M, Morillas-Ruiz J M. A review: inflammatory    process in Alzheimer's disease, role of cytokines. The Scientific    World Journal 2012; 2012:756357.-   [41] Kennaway D J. Potential safety issues in the use of the hormone    melatonin in paediatrics. Journal of paediatrics and child health    2015; 51:584-589.-   [42] Klein N, Kemper K J. Integrative approaches to caring for    children with autism. Current problems in pediatric and adolescent    health care 2016.-   [43] Kennaway D J. Are the proposed benefits of melatonin-rich foods    too hard to swallow? Crit Rev Food Sci Nutr 2015:0.-   [44] Monti J M, Pandi-Perumal S R. Eszopiclone: its use in the    treatment of insomnia. Neuropsychiatric disease and treatment 2007;    3:441-453.-   [45] MacFarlane J, Morin C M, Montplaisir J. Hypnotics in insomnia:    the experience of zolpidem. Clin Ther 2014; 36:1676-1701.-   [46] Singh H, Thangaraju P, Natt N K. Sleep-walking a rarest side    effect of zolpidem. Indian journal of psychological medicine 2015;    37:105-106.-   [47] Richey S M, Krystal A D. Pharmacological advances in the    treatment of insomnia. Curr Pharm Des 2011; 17:1471-1475.-   [48] Barrett J R, Tracy D K, Giaroli G. To sleep or not to sleep: a    systematic review of the literature of pharmacological treatments of    insomnia in children and adolescents with    attention-deficit/hyperactivity disorder. Journal of child and    adolescent psychopharmacology 2013; 23:640-647.-   [49] Liu A, Tipton R, Pan W et al. Tart cherry juice increases sleep    time in older adults with insomnia (830.9). The FASEB Journal 2014;    28:830.839.-   [50] Vuong Q V, Bowyer M C, Roach P D. L-Theanine: properties,    synthesis and isolation from tea. J Sci Food Agric 2011;    91:1931-1939.-   [51] Weeks B S. Formulations of dietary supplements and herbal    extracts for relaxation and anxiolytic action: Relarian. Medical    science monitor: international medical journal of experimental and    clinical research 2009; 15:RA256-262.-   [52] Street R A, Sidana J, Prinsloo G. Cichorium intybus:    Traditional uses, phytochemistry, pharmacology, and toxicology.    Evidence-Based Complementary and Alternative Medicine 2013; 2013.-   [53] Lyon M R, Kapoor M P, Juneja L R. The effects of L-theanine    (Suntheanine) on objective sleep quality in boys with attention    deficit hyperactivity disorder (ADHD): a randomized, double-blind,    placebo-controlled clinical trial. Alternative medicine review: a    journal of clinical therapeutic 2011; 16:348-354.-   [54] Rao T P, Ozeki M, Juneja L R. In search of a safe natural sleep    aid. Journal of the American College of Nutrition 2015; 34:436-447.-   [55] Bannai M, Kawai N. New therapeutic strategy for amino acid    medicine: glycine improves the quality of sleep. Journal of    pharmacological sciences 2012; 118:145-148.-   [56] Udenigwe C C, Aluko R E. Food protein-derived bioactive    peptides: production, processing, and potential health benefits.    Journal of Food Science 2012; 77:R11-R24.-   [57] Khiari Z, Ndagijimana M, Betti M. Low molecular weight    bioactive peptides derived from the enzymatic hydrolysis of collagen    after isoelectric solubilization/precipitation process of turkey    by-products. Poultry science 2014; 93:2347-2362.-   [58] Gómez-Guillén M, Giménez B, López-Caballero Ma, Montero M.    Functional and bioactive properties of collagen and gelatin from    alternative sources: A review. Food Hydrocolloids 2011;    25:1813-1827.-   [59] Kim S-K, Ngo D-H, Vo T-S. Marine fish-derived bioactive    peptides as potential antihypertensive agents. Adv Food Nutr Res    2012; 65:249-260.-   [60] Cooper C A, Brown K K, Meletis C D, Zabriskie N. Inflammation    and hyaluronic acid. Alternative & complementary therapies 2008;    14:78-84.-   [61] Wesotowska A, Nikiforuk A, Michalska K et al. Analgesic and    sedative activities of lactucin and some lactucin-like guaianolides    in mice. Journal of ethnopharmacology 2006; 107:254-258.-   [62] E I-Sayed Y S, Lebda M A, Hassinin M, Neoman S A. Chicory    (Cichorium intybus L.) root extract regulates the oxidative status    and antioxidant gene transcripts in CCI 4-induced hepatotoxicity.    PloS one 2015; 10:e0121549.-   [63] Aqil F, Ahmad I, Mehmood Z. Antioxidant and free radical    scavenging properties of twelve traditionally used Indian medicinal    plants. Turkish journal of Biology 2006; 30:177-183.

What is claimed:
 1. A method for improving one or more of the followingconditions in a human: onset of sleep, sleep depth, sleep quality, sleepduration, sleep apnea, or fatigue during the day; wherein said methodcomprises the human's orally consuming a dose of a composition; whereinthe composition comprises: (a) a first component comprising collagen, agelatin peptide, or the amino acid glycine; wherein the first componenthas an average molecular weight less than 3500 Dalton; (b) a secondcomponent comprising L-theanine; (c) a third component comprisinglactucopicrin, deoxylactucopicrin, or another lactucopicrin derivative;(d) a fourth component comprising hyaluronic acid; (e) a fifth componentcomprising epigallocatechin gallate; and (f) a sixth componentcomprising quinic acid; and wherein one or more of the followingconditions improves for the human: onset of sleep, sleep depth, sleepquality, sleep duration, sleep apnea, or fatigue during the day.
 2. Themethod of claim 1, wherein the composition additionally comprises anutritive or non-nutritive sweetener, and a flavoring agent; wherein theflavoring agent comprises as least one flavoring component other thanextract of tea (Camellia sinensis) and other than extract of chicory(Cichorium intybus).
 3. The method of claim 1, wherein one dose of thecomposition comprises: (a) 0.5 to 12 g collagen peptide; or 0.5 to 5 gglycine as amino acid; (b) a tea (Camellia sinensis) extract containing100 to 500 mg theanine; and 50 to 300 mg epigallocatechin gallate; and(c) 1-10 g chicory (Cichorium intybus) extract containing lactucopicrin,deoxylactucopicrin, or another lactucopicrin.
 4. The method of claim 1,wherein the composition is supplied in aqueous solution or aqueoussuspension; wherein the concentrations of the components of the aqueoussolution or aqueous suspension are such that 30-60 mL of the aqueoussolution or aqueous suspension supplies one dose of the composition. 5.The method of claim 4, wherein the composition additionally comprises anutritive or non-nutritive sweetener, and a flavoring agent; wherein theflavoring agent comprises as least one flavoring component other thanextract of tea (Camellia sinensis) and other than extract of chicory(Cichorium intybus).